This Mentored Clinical Scientist Development Award (MCSDA) application addresses the pathophysiology of neuropathic pain. Nerve injury-induced neuropathic pain is usually accompanied by mechanical allodynia and thermal hyperalgesia, which result in depression, anxiety and a marked decrease in quality of life. Analgesics such as non-steroidal anti-inflammatory drugs and opiates are relatively ineffective in treating neuropathic pain, a fact that reflects our poor understanding of this phenomenon. Several drugs with some effectiveness in reducing neuropathic pain also significantly modulate intracellular calcium levels in sensory pathway cells. Targeting intracellular calcium mechanisms more directly may thus provide novel therapeutic options in neuropathic pain. Intracellular calcium regulatory mechanisms are often uniquely sculpted to serve cell-specific functions, yet surprisingly little is known about intracellular calcium homeostasis in sensory pathway cells of the dorsal root ganglion and spinal cord. The lack of approaches for preventing the development of neuropathic pain or to adequately control established neuropathic pain underscores the importance of understanding normal and injury-induced changes in the intracellular calcium regulation of sensory pathway cells. Our long-range goal is to develop effective strategies for preventing the development of and reversing established neuropathic pain. The objective of this application is to determine the contribution of altered intracellular Ca2+ regulatory mechanisms in sensory pathway cells and the development of neuropathic pain. The central hypothesis of the proposed research is that injury-induced changes in endoplasmic reticulum (ER) calcium sequestration and release mechanisms of dorsal root ganglion (DRG) cells and spinal cord dorsal horn sensory neurons underlie the development of nerve injury-induced neuropathic pain. We plan to test our hypothesis and accomplish the objective of this application by pursuing the following three specific aims. (1): To determine whether nerve injury-induced neuropathic pain alters intracellular calcium homeostasis in rat DRG neurons. (2): To determine whether nerve injury-induced neuropathic pain alters intracellular calcium homeostasis in rat spinal cord. (3): To determine whether thapsigargin, an ER calcium pump inhibitor, can reverse nerve injury-induced neuropathic pain.